Nozaki Haruka, Sakakibara Nana, Hanafusa Hiroaki, Inoki Yuta, Tanaka Yu, Kitakado Hideaki, Ueda Chika, Nagano China, Horinouchi Tomoko, Yamamura Tomohiko, Ishimori Shingo, Yamaguchi Hiroshi, Nozu Kandai, Morisada Naoya
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; Kobe University School of Medicine, Kobe, Japan.
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Brain Dev. 2025 Aug;47(4):104366. doi: 10.1016/j.braindev.2025.104366. Epub 2025 May 9.
Cases of unexplained neurodevelopmental disorder (NDD) are often accompanied by multiple congenital anomalies. With recent advances in genetic analysis technology, whole-exome sequencing (WES) has become a powerful diagnostic tool for unexplained NDD patients, but variants of unknown significance are sometimes detected in them.
WES identified a variant in a 2-year-old boy with NDD associated with multiple congenital anomalies who had no abnormal findings in G-banding and array comparative genomic hybridization (array CGH). mRNA analysis was performed on the variant using the patient's peripheral blood leukocytes following in silico analysis to confirm its effect on splicing.
WES revealed a novel homozygous single base substituting variant of unknown significance (VUS), which was carried heterozygously by the patient's parents (DCPS, NM_014026.6: c.200A>G, p.(Lys67Arg)). In silico analysis predicted that this variant may cause aberrant splicing, and mRNA analysis revealed a 48-bp deletion from the 3' end of exon 1. Biallelic variants of DCPS are known to cause Al-Raqad syndrome, a quite rare disorder which presents NDD with multiple malformations. This disease has been reported in only eight individuals from five Middle Eastern or Caucasian families but never in the Japanese but the symptoms of the present case were similar to reported cases of this syndrome.
We successfully diagnosed a case of unexplained NDD as Al-Raqad syndrome by WES along with mRNA analysis. Single base substitution with judged VUS can be pathogenic by causing aberrant splicing and, therefore, in silico analysis and subsequent RNA sequence are necessary to prove its pathogenicity.
不明原因的神经发育障碍（NDD）病例常伴有多种先天性异常。随着基因分析技术的最新进展，全外显子测序（WES）已成为诊断不明原因NDD患者的有力工具，但有时会在这些患者中检测到意义未明的变异。
WES在一名患有NDD并伴有多种先天性异常的2岁男孩中鉴定出一种变异，该男孩在G显带和阵列比较基因组杂交（阵列CGH）中未发现异常。在进行计算机分析后，使用患者的外周血白细胞对该变异进行mRNA分析，以确认其对剪接的影响。
WES揭示了一种新的意义未明的纯合单碱基替代变异（VUS），患者父母为该变异的杂合携带者（DCPS，NM_014026.6：c.200A>G，p.（Lys67Arg））。计算机分析预测该变异可能导致异常剪接，mRNA分析显示外显子1的3'端缺失48个碱基对。已知DCPS的双等位基因变异会导致Al-Raqad综合征，这是一种非常罕见的疾病，表现为NDD伴多发畸形。仅在来自五个中东或高加索家庭的八个人中报道过这种疾病，在日本人中从未报道过，但本病例的症状与该综合征的报道病例相似。
我们通过WES和mRNA分析成功地将一例不明原因的NDD诊断为Al-Raqad综合征。判断为VUS的单碱基替代可通过导致异常剪接而具有致病性，因此，计算机分析和后续的RNA序列分析对于证明其致病性是必要的。
